The objective of this project is to define the key mechanisms leading to hypoxic-ischemic brain injury in the human newborn. Clinical and experimental studies show that after an initial recovery in brain energy metabolism there is a secondary decline that may extend for months What are the key mechanisms responsible for early and late brain injury and can any aspect of the injury process by reduced by therapeutic intervention are clinical priorities addressed in this proposal. We will continue to study the immature rat model of cerebral hypoxia-ischemia. The central focus is to determine how inflammation before hypoxia-ischemia as well as inflammation induced by the consequences of brain injury contribute to progressive brain damage. As brain injury in the neonate is strongly associated with exposure to infection in utero, we will mimic the neuro- inflammation effects of systemic infection by giving immature rates lipopolysaccharide (LPS). Evaluations will include systemic and cerebral analyses of giving immature rats lipopolysaccharide (LPS). Evaluation will include systemic and cerebral analyses of giving immature rats lipopolysaccharide (LPS). Evaluations will include systemic and cerebral analyses of inflammatory cells (neutrophils and microglia), cytokines, nuclear transcription factor NF-kappaB activation, brain lipid peroxidation, and disturbances in brain iron metabolism. Mice lacking the receptor for IL-1 will aid in defining IL-1's role in the response to LPS as will anti-cytokine treatment. Specific Aims include: Aim 1: To establish the systemic and cerebral inflammatory responses of immature rats to infections of LPS. Aim 2: To expose immature rats to a combination of LPS and cerebral hypoxia-ischemia to determine whether or not the combined stress accentuates hypoxic-ischemic brain damage in the immature rat. Aim 3: To investigate how nitric oxide contributes to Poly (ADP-ribose)polymerase (PARP) activation and delayed brain energy failure following hypoxia-ischemia and LPS administration in the immature rat. Aim 4: To characterize the chronic neuropathologic alterations which result from cerebral hypoxia-ischemia in the immature rat. Our investigations also will include in vivo sequential MR imaging ant 31P NMR spectroscopy to measure the progression of cerebral atrophy and energy failure in the same rats over the first year of recovery. We will use pharmacologic agents in vivo to test the contribution of key injury mechanisms, including drugs directed at cytok9ines, free radicals, iron nitric oxide, and PARP. We will use biochemical, histologic, and neuropathologic techniques to determine if LPS primes the brain for greater ischemic injury and if a chronic damaging inflammatory process is induced by the primary insult.